Nutrient signalling and longevity

The only physiological manipulation that is currently known to extend mammalian lifespan is dietary restriction. In worms, flies and mammals reduced activity in the core insulin/IGF signalling pathway increases lifespan.

This pathway converges on the protein kinase mTOR, which serves as ‘master switch’ in eukaryotic metabolism and growth. When mTOR is active it represses autophagy and promotes anabolic metaboIism, including protein synthesis.

When mTOR is inactive (e.g. during nutrient starvation) or inhibited, cells switch to a catabolic mode; autophagy is activated to recycle proteins and organelles and protein synthesis is repressed (Figure 1, right).

In a landmark study Harrison and co-workers demonstrated that pharmacological inhibition of mTOR, with the drug rapamycin, extended the lifespan of mice, even when administered relatively late in life (Harrison et al. Nature. 2009; 460:392-395)

We are interested in understanding the cellular and molecular basis of the lifespan extension observed upon chronic mTOR inhibition. Concomitant with the induction of autophagy (see the Ktistakis Group webpage), nutrient starvation or mTor inhibition (which both extend lifespan) also repress protein synthesis.

However, protein synthesis is not shut down – this would not be compatible with lifespan extension. Indeed, mTOR inhibition can actually up-regulate stress response genes, some of which are also implicated in anti-oxidant responses and lifespan extension. We are interested in understanding the cellular and molecular basis of the lifespan extension observed upon chronic mTOR inhibition.

Nutrient starvation also activates the mitogen-activated protein kinases (MAPKs, e.g. ERK1/2) and the stress-activated protein kinases (SAPKs, e.g. JNK and p38). We are interested in how these pathways are activated and their role in the nutrient starvation.

On the one hand these pathways can, under some conditions, elicit irreversible cellular senescence, which is not compatible with lifespan extension. Other studies suggest that they may be involved in regulating autophagy which has been implicated in promoting lifespan extension.

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